The immune system is central to a wide variety of disease states, ranging from protective responses to microbial infections and some tumors; to unwanted inflammation and immunopathology characteristic of autoimmunity, organ transplantation rejection reactions, and allergic conditions. A better understanding of the immune system and how to regulate its activity is needed both to create better vaccines in cases of insufficient protective immunity, and to specifically down modulate immune responses to limit syndromes that result from an overzealous recognition of "non-dangerous" antigens. Based on the success of the initial 5- year award, the ultimate goals of this COBRE renewal application are: 1) to recruit additional, and to continue to mentor already recruited, faculty investigators who are engaged in immunological research and are/will be competitive in securing NIH and other extramural funding, and 2) to establish a Center for Molecular, Cellular, and Translational Immunological Research that will be nationally recognized and free standing in five years. With the foundation of a long-standing Immunology Program, which has now been substantially enhanced by initial COBRE support, this proposal takes advantage of a highly interactive Core of existing collaborative faculty at Dartmouth Medical School (DMS) and Dartmouth Hitchcock Medical Center (DHMC). With this base continuation of the COBRE mechanism will provide the resources to further grow the Program and facilitate inter-disciplinary immunological research in four ways: 1) recruitment of three or more tenure-track faculty; 2) mentored development of new investigators previously supported by COBRE, and the four promising junior investigators who are proposed as the Project Leaders of the individual Research Projects: these Projects exhibit the multi-disciplinary breadth characteristic of a Center but also are intertwined by the common theme of modulation of immunity in various disease states, both at the level of innate immunity/non-specific inflammatory processes as well as with respect to specific adaptive immunity; 3) building enhanced research infrastructure via expansion of the COBRE Cores and their full integration with the complementary Cores and shared services of the Morris Cotton Cancer Center, the new Immunotherapy Center, and the "Lung" COBRES at Dartmouth and the University of Vermont; and 4) synergistic scientific collaboration through the four COBRE Research Projects, associated Cores, and other basic and translational infrastructure and programs at DMS/DHMC. Together with substantive institutional commitment by DMS/DHMC, there is confidence that the strong existing cadre of investigators, already expanded and matured by the COBRE mechanism, can be further developed to establish a Center for Immunological Research that both is grounded in excellent basic investigation and also embraces a translational approach to promote bidirectional bench-to-bedside application of hypothesis-driven research. [unreadable] [unreadable] [unreadable]